Diphenyl sulfones

ABSTRACT

NEW SUTSTITUTED DIPHENYL SULFONES USEFUL IN REDUCING MORTALITY AND DECREASING LESION INCIDENCE OF POULTRY EXPOSED TO MAREK&#39;&#39;S DISEASE ARE DISCLOSED.

United States Patent Ofice 3,775,403 DIPHENYL SULFONES Tsung-Ying Shen,Westfield, William V. Ruyle, Scotch Plains, Michael W. Fordice, Clark,and Norman P. Jensen, Watchung, N.J., assignors to Merck & Co., Inc.,Rahway, NJ. No Drawing. Filed Sept. 17, 1970, Ser. No. 73,245 Int. Cl.C07d 31/48 US. Cl. Mil-239.8 9 Claims ABSTRACT OF THE DISCLOSURE Newsubstituted diphenyl sulfones useful in reducing mortality anddecreasing lesion incidence of poultry exposed to Mareks disease aredisclosed.

New substituted diphenyl sulfones of the following formula:

wherein Z is a substituted amino moiety having the following structure:

wherein R is a phenyl group, optionally substituted with chloro; hydroxyand loweralkoxy; or hydroxy and chloro; or with a 3,4-methylenedioxysubstituent; or a heterocyclic -6 membered ring containing one heteroatom selected from the group consisting of O, N, or S;

R is cycloalkyl having 3-6 carbon atoms, trifluoromethyl, chloromethyl,a heterocyclic 5-6 membered ring containing one hetero atom selectedfrom the group consisting of O or N, or an aminohydrocarbyl fragmentselected from the group consisting of aminomethyl, 1-amino-Z-phenylethyl, and l-amino-Z-carboxyethyl; R is also2-carboxyethyl; and

3,775,403 Patented Nov. 27, 1973 The compounds of Formula I (above)which are the sodium bisulfite and methanol adducts, i.e.,

respectively, are also within the scope of this invention. Thesesulfones are useful in reducing mortality and decreasing lesionincidence of poultry exposed to Mare-ks disease. In addition to the newcompounds, compositions comprising the new sulfones as the activeingredient are provided.

DISCUSSION OF THE PRIOR ART Derivatives of diamino-diphenyl sulfone havebeen described in the literature for many years; see B. H. Northey,Sulfonamides, A.C.S. monograph No. 106 (New York, 1948).

SUMMARY OF THE INVENTION This invention provides new substituteddiphenyl sulfones of the following formula:

wherein Z is a substituted amino moiety having the following structure:

The compounds of Formula I (above) which are the sodium bisulfite andmethanol adducts, i.e., having the following probable structures:

respectively, are also within the scope of this invention.

Mareks disease is a highly infectious lymphoproliferative disorder ofpoultry, especially chickens. Mareks disease has also been known asneural leukosis, neuralymphomatosis, acute avian leukosis, and skinleukosis. The causative agent(s) are viral with a cell associatedHerpestype virus definitely implicated as an etiological factor. Mareksdisease usually is clinically evident in birds prior to sexual maturity,i.e., before the first egg is laid. Clinical manifestations may be oneor more of these signs: regional or generalized paralysis, diarrhea withfecal staining of posterior abdominal feathers, weight loss, dyspnea,blindness, enlarged abdomen, or death.

The lesions evident are non-necrotic and include one or more of thefollowing: lymphocytic infiltrated peripheral nerves and/or featherfollicles, lymphoproliferative foci, microscopic to several mm. in size,within any tissue of the body but principally within the liver, spleen,kidney, gonads, heart, proventriculus, breast muscle, skin, and nerves.

Mareks disease is estimated by the US. Department of Agriculture tocause a $200 million annual loss to the US. poultry industry. This lossis due to mortality and to the rejection of slaughtered bird carcassesas being unfit for human consumption. This rejection is due to thepresence of the lymphoproliferative foci.

OBJECTS OF THE INVENTION It is an object of this invention to providenovel diphenyl sulfone compounds which have utility as agents useful inthe treatment of poultry exposed to Mareks disease. It is a furtherobject of this invention to provide a composition, which whenadministered orally to poultry, reduces mortality and decreases lesionincidence of poultry exposed to Mareks disease. It is a further objectof this invention to provide a composition containing a specific levelof novel diphenyl sulfone compounds which accomplishes the positiverelief without adverse effects of residue or toxicity. It is a stillfurther object of this invention to provide a composition containingnovel diphenyl sulfone compounds which promote the growth of poultrywhen orally administered. It is yet another object of this invention toprovide a new veterinary use for novel diphenyl sulfone compounds as agrowth promotant of poultry. Other objects of the invention will beapparent upon further reading.

PREFERRED ASPECTS OF THE INVENTION The preferred novel compounds of thisinvention are those in which Z is H R1C=N More preferably, Z is when Ris a heterocyclic 5-6 membered ring having one hetero atom selected fromthe group consisting of O, N, or S. It is readily seen that R ispreferably a pyrrolyl-, pyridinyl-, fur-anyl-, pyranyl-, thienyl-, orthiapyranyl-radical. The optimal compounds are those in which R ispyridinyl-, or thienyl-. Another preferred compound is that in which Ris furanyl-.

Another group of preferred compounds of this invention are those inwhich R, is a phe y g p, or a stituted phenyl group, the substituent(s)on the phenyl group being chloro-, or hydroxy and loweralkoxy, or chloroand hydroxy. These substituent(s) can be located anywhere on the phenylmoiety. The most preferred R is a phenyl substituted with hydroxy andloweralkoxy. By the term loweralkoxy is meant a group having 1-6 carbonatoms. The most preferably loweralkoxy group is methoxy. The optimalcompound is 4-(2-hydroxy-3- methoxybenzilidene)-4'-ureido-diphenylsulfone, 4-(3-methoxy-4-hydroxybenzilidene) 4-ureido-diphenyl sulfone,or 4-(2-chlorobenzilidene)-4-ureido-diphenyl sulfone.

As discussed above, the sodium bisulfite or methanol adducts of thecompounds Where Z is R1 (i =N are included within the scope of thisinvention. Particularly, preferred adducts are those of the compoundslisted above. For instance, preferred compounds are 4-(l-methoxypyridinylidene)-4'-ureido-diphenyl sulfone, 4- [l-(sodiumsulfite)-pyranylidene] -4'-ureido-diphenyl sulfone, 4-[1-(sodiumsulfite)-furanylidene] 4 ureido-diphenyl sulfone, 4 [1 (sodiumsulfite)-benzilidene]-4'- ureido-diphenyl sulfone, and4-(1-methoxy-2-chlorobenzilidene)-4-ureido-diphenyl sulfone.

Another preferred compound when Z is is that in which R is a phenylgroup having a methylenedioxy substituent at 3,4. This compound, and thesodium sulfite and methanol adducts, are useful also against Mareksdisease.

Another group of preferred compounds of this invention are those inwhich Z is ll H Rz-CN- is that in which R is chloromethyl-; thiscompound is known as 4-chloroacetamido-4'-ureido-diphenyl sulfone. R canalso be a haloloweralkyl group, wherein loweralkyl has 1-6 carbon atoms.

Still another group of preferred compounds when Z is l H Rz--N- arethose in which R is a heterocyclic 5-6 membered ring containing onehetero atom. The hetero atom is O or N. Preferred heterocyclic moietiesare, for example, furan, pyrrole, pyran, and pyridine. Most preferred is4-furoylamino-4'-ureido-diphenyl sulfone. Another compound is4-pyridinoylamino-4-umido-diphenyl sulfone.

Yet other preferred compounds in this series, where Z is are those inwhich R is an aminohydrocarbyl fragment selected from the groupconsisting of aminomethyl, 1- amino-Z-phenylethyl, andl-amino-Z-carboxyethyl. Another preferred compound is that in which R is2-carboxyethyl.

Another preferred compound of this invention is that in which Z is It isapparent that soluble non-toxic salts and alcoholate solvates of all ofthe above compounds are also included within the scope of the invention.

The novel diphenyl sulfones of this invention are generally prepared bya condensation reaction of 4-(sulfanilyl) phenyl urea with anappropriate reactant.

To prepare compounds of the type when Z is an aldehyde having theformula R CHO' is employed. The reactants are used in approximatelyequimolar quantities and mixed in a suitable organic solvent, such asethanol, methanol, propyl alcohol, isobutyl alcohol, and others.Generally, any polar organic solvent which will not participate in thereaction is preferred. The reactants are mixed with slight heating,i.e., from 30-150 C., preferably from 30100 C., for from /2-20 hours.The crude product is collected as a precipitate and purified.

When Z is the corresponding preferably chloride, is used. This reactantcan generally be described as the acid halide or chloride, and thecorresponding acid anhydride is also suitable.

Whether the acid halide or acid anhydride is used, these reactants areeach employed in approximately equimolar quantities with thesulfaguanidine. A solvent is employed, for instance, acetone,N,N-dimethylformamide, pyridine, trifiuoroacetic anhydride and others.The temperature of the reaction can be from ambient to 150 C. and ispreferably at room temperature to 90 C. The product can generally berecovered as a solid precipitate, or by evaporation of the solvent. Thereaction goes to completion within 30 minutes to 20 hours.

The compounds when Z is chosen from one of the moieties III through VIIIare prepared generally as discussed above, using an appropriatereactant. For instance, the compound4-(2-nitrophenysulfenyl)-4'-ureido-diphenyl sulfone, when Z issubstituent VII, is prepared by reacting 2-nitrophenylsulfenylchloridewith 4-(sulfanilyl) phenyl urea.

The compound 4-( l-methyl-1,2-butenyl-3-one)amino- 4'-ureido-diphenylsulfone, when Z is substituent VIII, is

prepared by reacting 4-(sulfanilyl)phenyl urea with 2,4- pentanedione.An optional solvent such as methanol, ethanol, or tetrahydrofuran isemployed. The reaction can also be conducted in an excess of the2,4-pentanedione. An acidic catalyst, such as toluenesulfonic acid or2,4- dinitrobenzene sulfonic acid, can also be employed if desired. Thereactants are heated at room temperature at C. for 2-15 hours.

The compound, 4-(dimethylaminomethyleneamino)-4'- ureido-diphenylsulfone, when Z is substituent III, is prepared by acid hydrolysis ofN'-dimethylaminomethylene- N [4(p-dimethylaminomethyleneaminosulfonyl)phenyl]urea. The latter compoundis obtained by reacting dimethylformamide and p-sulfanilylphenyl urea inthe presence of phosphorus oxychloride.

The compound, 4-benzylamino 4' ureido-diphenyl sulfone, when Z issubstituent IV, is prepared by first reacting dibenzylphosphite andN-bromosuccinamide and then adding this reaction product to4-(sulfanilyl)phenyl urea in an organic solvent. The reactions allproceed at room temperature.

The compound,4-(B-carboxy-B-acetylaminoethylthiomethylamino)-4-ureido-diphenylsulfone, sodium salt, when Z is substituent V, is prepared by reactingcysteine and 4-(sulfanilyl)phenyl urea in the presence of formaldehydefollowing the same general condensation process conditions.

The compound, 4-cinnamylidene 4 ureido-diphenyl sulfone, when Z issubstituent VI, is prepared as are the Schilfs base-type compounds bythe reaction of cinnamic aldehyde and 4-(sulfanilyl)phenyl urea.

Novel diphenyl sulfones of the type disclosed above are effective in thetreatment and control of Mareks disease. The compounds effectiveness istested in vivo by employing chickens which have been infected with viruscontaining lymphoblasts originally obtained from a chicken with atypical case of Mareks disease. The test procedure is as follows:Athens-Canadian (A-C) random bred chicks, in groups of five each, wereplaced in cages with Wire floors. They were fed ad libitum a standardpoultry ration in which concentrations of the sulfones were blended justprior to use. Normal and infected control birds were fed basal rationcontaining no test compound. After 24 hours on medication, the chickswere injected with a challenge inoculum of Mareks disease virus. Theinoculate was originally obtained from a typical field case of Mareksdisease in commercial broilers. The inoculate characteristicallyproduces lymphoid tumors of the liver, spleen, kidney, and gonads.

The oral medication in the feed is continued throughout the experimentas a stated percentage of the diet. After an appropriate experimentalperiod, wherein over 50% of the non-medicated infected controls succumb,all surviving birds are sacrificed. All dead and sacrificed birds areautopsied and lesion incidence recorded.

In accordance with this invention, the novel diphenyl sulfones areemployed for controlling Mareks disease by administering them to poultrysusceptible or exposed to the disease, either in the drinking water,feed, or parenterally. The preferable mode of administration is orally,either in the drinking water or feed.

It is most preferred to disperse the diphenyl sulfone in the finishedfeed of the animals, and to administer the medicated feed ad libitum tothe birds. Good results against Mareks disease are achieved withfeedstuif containing from about 0.002% to 0.1 by weight of the drug.Drug levels can also operably be from 0.0002% to 0.2% in the feed. Thepreferred range is between 0.01% to 0.1% in the feed. Levels in poultryfeed are here expressed in terms of percent by weight concentration.

The higher levels may be used in treating an established outbreak ofMareks disease, but the higher dosages are not preferred forprophylactic treatment where medicated feed is given continuously to thepoultry. It will be appreciated by those skilled in this art that theselow levels will eliminate any toxicity or residue problems which resultfrom feeding of high levels of the diphenyl sulfone.

'Ihe finished feed in which the above-described levels of the noveldiphenyl sulfones are employed is a nutritionally adequate onecontaining sources of carbohydrate, protein, fat, vitamins, minerals andother nutritional factors commonly employed in commercial poultryraising. In addition, other poultry feed additives such as cccidiostats,e.g., amprolium, ethopabate, nicarbazin, can be employed in thecompositions.

In addition to administration via the solid feedstulf, diphenyl sulfonescan be administered to poultry by incorporation in the drinking water.The preferred dose levels in the drinking water are usually somewhatless than those employed in a solid feed inasmuch as poultry drink abouttwice as much as they eat. The operable level in drinking water is from0.0001% to 0.1% by weight of the diphenyl sulfone compound and thepreferred range is 0.005% to 0.1% by weight. Administration via thedrinking water is of advantage when using the compound therapeuticallyrather than prophylactically. For this purpose it is convenient toprepare dispersible or water-soluble powders in which the diphenylsulfones are intimately dispersed in a suitable water-soluble ordispersible liquid or solid carrier such as dextrose, sucrose, dimethylsulfoxide, or other suitable non-toxic carriers, at concentrations offrom about 0.03% to about 25% by weight. These solids may then beconveniently added to the drinking water by the poultry grower.

A typical drinking water formulation contains 4(thenylidene-Z)-4'-ureido-diphenyl sulfone( 0.3%; l-(2-n-propyl-4-amino-5-pyrimidiny1-methyl)-2-methyl pyridinium chloridehydrochloride, 9.6%; dextrose, 30%; propylene glycol, 20%;dimethylpolysiloxane, 0.002%; polyoxyethylene sorbitan monoleate, 0.2%;water, to 100%.

According to a further aspect of this invention, there are providedcompositions comprising poultry feed supplements or additives containingthe diphenyl sulfones previously described as an elfective Mareksdisease agent. In such compositions the compound is mixed with ordispersed in an orally ingestible carrier vehicle that is nontoxic tothe poultry and compatible with the finished feedstuff. These feedsupplements contain a significantly higher percentage of the noveldiphenyl sulfone compounds than does the finished feed, and are mixedwith or blended into the feedstutt' before administration to thepoultry. In order to assure uniform distribution of the compound in thefinished feed, it is customary to employ an intermediate dilution stepin which the supplement is blended with a portion of the final feed, andthis intermediate mix is then added to the remainder of the feed withadequate mixing. The diphenyl sulfones described hereinabove may beformulated into feed supplement compositions containing from about 0.05%to about 50% by weight of drug. It is preferred in the industry to usefrom about 1-5 pounds of such a supplement per ton of feedstutf. Itwill, therefore, be appreciated that the preferred supplementconcentration will depend to a large extent on the final use leveldesired. With the compounds of this invention, feed supplementcompositions containing from about 1.0% to about 20% by weight of activeingredient are preferred.

Diluent or carrier vehicles that may be used in these poultry feedsupplements are solid orally ingestible poultry feed additives such ascorn meal, distillers dried grains, ground oyster shell, citrus mealfermentation residues, wheat shorts, wheat middlings, molasses solubles,corn gluten feed, soybean meal, dehulled soya flour, crushed limestone,fermentation mycelia, edible vegetable substances and the like.Nutritive carriers are preferred since the finished feed is benefittedthereby.

It will be apparent to one skilled in the art that when we use the termsubstituted diphenyl sulfone we mean compounds which can also be namedas derivatives of 4- 8 (sulfanilyl)phenyl urea. The 'sulfanilyl portionof the molecule is and the phenyl and urea portions areself-explanatory. When the latter system of nomenclature is used, thenovel compounds of this invention are named as the N-substituents. Forinstance, the compound described in Example 1,4-(furanylidene-Z)-4'-ureido-diphenyl sulfone can also be named4-[N-(furanylidene-2)-sulfanilyl]phenyl urea. The other compounds can benamed accordingly.

This invention will be more fully described in the following examples.

EXAMPLE 1 4-(furanylidene-2)-4-ureido-diphenyl sulfone 1.5 g. offuran-Z-carboxaldehyde is dissolved in 50 ml. of ethanol and 2.1 g. of4-(sulfanilyl)phenyl urea is added. The solution is boiled toconcentration to a volume of 15 ml., then cooled. A precipitate formsduring the concentration and is collected and washed with ethanol.Recrystallization of the solid from 40 ml. of methanol yields theproduct, 4-(furanylidene-2)-4'-ureidodiphenyl sulfone, M.P. 188190 C.

EXAMPLE 2 4-(thenylidene-2)-4-ureido-diphenyl sulfone A 1.2 g. portionof thiophene-2-carboxaldehyde is dissolved in 50 ml. of ethanol and 2.00g. of 4-(sulfanilyl) phenyl urea is added. The solution is boiled downto 15 ml. and cooled. The resultant precipitate is collected; washedwith hot ethanol. Recrystallization from 35 ml. of methanol gives theproduct, 4(thenylidene-Z)-4'-ureidodiphenyl sulfone, M.P. 220-222 C.

EXAMPLE 3 4-(pyrrolylidene-3)-4'-ureido-diphenyl sulfone Using the sameprocedure of Examples 1 and 2, pyrrole- 3-carboxaldehyde is reacted with4-(sulfanilyl)phenyl urea. The product,4-(pyrrolidene-3)-4'-ureido-diphenyl sulfone is recovered.

EXAMPLE 4 4-(pyridinylidene-2)-4'-ureido-diphenyl sulfone, methanoladduct EXAMPLE 5 4-(pyranylidene-3)-4'-ureido-diphenyl sulfone, methanoladduct Using the procedure of Example 4, pyran-3-carboxaldehyde isreacted with 4-(sulfanilyl)phenyl urea. The product,4-(pyranylidene-3)-4-ureido-diphenyl sulfone, methanol adduct isrecovered.

EXAMPLE 6 4-(thenylidene-2)-4'-ureido-diphenyl sulfone, sodium bisulfiteadduct 8.0 millimoles of thiophene-Z-carboxaldehyde and 5 millimoles ofNaHSO are heated with 5 millimoles of 4- (sulfanilyl)phenyl urea in 10ml. of water on a steam bath for 10 minutes. During this time, anadditional 5.0 millimoles of thiophene-Z-carboxaldehyde is added. The

10 mixture is then cooled and insolubles are removed by is cooled anddiluted with 140 ml. of water. A viscous oil filtration. The filtrate isconcentrated to a solid by freezis separated. The supernatant isdecanted and replaced ing and then drying under vacuum (freeze-drying).with more water. After stirring overnight, the oil is solidi-Purification is achieved by dissolving in methanol and fied and iscollected on a filter. The solid is dissolved in reprecipitating withether. The product, 4-(thenylidene- 5 100 ml. of acetone, the solutionis filtered to remove in- 2)-4-ureido-diphenyl sulfone, sodium bisulfiteadduct is solubles, and concentrated to 50 ml. The solution is thenrecovered having a melting point of 117 C., dec. The cooled. Aprecipiate is recovered which is pure by thin compound is fullyidentified by means of NMR techlayer chromatography analysis. Theproduct, 4-cycloniques. hexanoylamino-4'-ureido-diphenyl sulfone isidentified by EXAMPLES NMR, M.P. 140l45 C. The following Examples 7-20are summarized and EXAMPLE 24 tabulated in Table I. Examples 7, 9, and14 through 17 4-cyclobutanoylamino- -ureido-diphenyl sulfone are thesodium bisulfite adducts of the indicated products and are preparedfollowing the procedure of Example 6. Examples 8 and 10 through 13 arethe unsubstituted Using the same process as described in Example 23,4-(sulfanilyl)phenyl urea and cyclobutanecarbonyl chloride are reacted.The product, 4-cyclobutanoylamino-4'- S f yp compounds prepared followmgthe ureido-diphenyl sulfone, has a melting point of 100 c. cedllres ofExample 1 F PP 18 through are with decomposition. The product wasidentified using the methanol adducts of the indicated products and areNMR prepared following the procedure of Example 4.

20 EXAMPLE These compounds were all 1dentlfied by use of nuclearmagnetic resonance techniques. Melting points of the in- 4furoylammo4'ureldo'dlphenyl sulfone dicated compounds were not obtainable, due tothe deg- POrtIOn 0f yDp y1ureais dissolved composition of the compoundunder heat. in 10 ml. of pyridine and 0.99 g. of furoyl chloride isTABLE I.-EXAMPLES 7-20 M.P. of product, Ex. No. Product obtainedStarting aldehyde C,

4-(iuranylidene-2)-4-ureido-diphenyl sulfone, NaHSOg adductFuran-2carboxaldehyde 4-(benzilidene)-4-ureido-diphenyl sulioneBenzaldehyde 223-225.5 d-(benzilidene)4-ureido-diphenyl sulfone, NaHSOaadduct do 4-(2-hydroxy-3-methoxy benzilidene)-4-ureido-diphenyl sulione.2-OH-3-O CH -benzaldehyde 210-212 114-(Z-hydroxy-fi-chlorobenzilidene)-4'-ureido-diphenyl sulfone2-OH-5-Cl-benzaldehyde 201-204 124-(4-ch1orobenzilidene)-4.-ureidodiphenyl sulfone 4-Cl-benzaldehyde 2103-110 13 4-(3,4-methylenedioxybenzilidene)-4-u.reido-diphenyl sulfone3, l-methylenedioxybenzaldehyde 231-233 144-(2-ehlorobenzilidene)-4-ureidodiphenyl sulfone, NaHSOa adduct.Z-OI-benzaldehyde 15 4-(fi-amethoxy4-hydroxybenzilideue)A-n.reido-dipheny1 sulfone, NaHSOs 3-0 (lHs-i-OH-benzaldehyde ad net. 16.4-(3d4gmethylenedioxybenzilidene)-4-ureido-diphenyl sulfone, NaHSOa3,4-methylenedioxybenzaldehyde a not. 174-(2-hydroxy-fi-methoxybenzilidene)-4-u.reldo-diphenyl sulfone, NaHSO;2-OH'3-OCH -benzaldehydee adduct. 18 4-(benzilidene)-4'-ureido-d.iphenylsulfone, methanol adduct"; Beuzaldehyde 194-(2cilaydroxy-3-methoxybenzilidene)-4-ureido-diphenyl sulione, methanol2-OH3-0CH3-benzaldehyde a not. 204-(zihydroxyi-chlorobenzilidene)-4-ureido-diphenyl sulfone, methanol2-OH-4-Cl-benzaldehyde a duct.

1 Not obtainable. i Decomposition.

added. The mixture is heated in a steam bath for 15 hours. EJQMPLE 21After cooling, 140 ml. of water is added. A dark oil 4- rifl r p y1sulfone separate which solidifies on standing to give 2.65 g. of Asuspension of 2.9 g. (10 mmoles) of 4-(sulfanilyl) solid. This materialis then dissolved in 20 ml. of methanol phenyl urea in 20 ml. oftrifluoroacetic anhydride is and the solution is filtered. Water isadded until cloudiness stirred overnight at room temperature. Theprecipitated is obtained, and the mixture is concentrated by heatingsolid is removed by filtration at the end of the reaction, under astream f ni g v Th residue, a r purlficatlofl, washed with ether, andrecrystallized from methanolyielded the product,4-furoylamino-4-ure1do-d1phenyl sulwater to give the product,4-trifiuoroacetamido-4-ureidofone, M.P. 138-145 C. diphenyl sulfone,M.P. 180 C. (softening and decom- EXAMPLE 26 position) 200 C. (allmelted). I

EXAMPLE 22 4-n1cotlnoylam1no-4 -ureldo-diphenyl sulfone A 2.00 g.portion of 4-(sulfanilyl)phenyl urea is dis-4-Ch10f0acetamid'4"l1reid-diPhenY1 Sulfone solved in 8 ml. of pyridineand 1.71 g. of nicotinoyl chlo- To a suspension of 11.6 g. of4-(sulfanilyl)pheny1 urea ride hydrochloride is added. The mixture iswarmed on a in 200 ml. of water containing 2 g. of sodium hydroxide,steam bath for 5 minutes. After cooling, 25 ml. of water is added 25 ml.of chloroacetylchloride. The reaction is added slowly and the resultantprecipitate is collected mixture is stirred at room temperature for onehour at on a filter. After washing successively with water and hot whichtime thin layer chromatography shows no presence methanol, 1.20 g. ofproduct, 4-nicotinoylamino-4'-ureidoof the starting material. Theproduct is recovered from diphenyl sulfone, is obtained, M.P. 220-2215C. the reaction mixture by filtration and purified by recrystal- EXAMPLE27 l1zatlon 1n methanol-water. The product,4-chloroacetamido-4-ureido-diph'eny1 sulfone, is recovered as the hemi-'PY Y P Y Sui-0116 hydrate, M.P. 195-197 C., dec. Using the same processas in Example 26, 4-(sulfanilyl) EXAMPLE 23 phenyl urea and pyroylchloride are reacted. The product,

4-pyroyl-4-ureido-diphenyl sulfone, is recovered.4-cyclohexanoylamino-4'-ureido-dipheny1 sulfone 7 EXAMPLE 28 To a warmsolution of 2.91 g. of 4-(sulfan1lyl)phenyl urea in 10 ml. of pyridineis added 1.11 g. of cyclohex- 4'PYHOIOYI'4 'ureldo'dlphenyl Sulfone Ianecarbonyl chloride. The mixture is heated on a steam Using the sameprocess as in Example 26, 4-(sulfanilyl) bath for 15 hours and anadditional 1.1 g. of the chloride phenyl urea and pyrroloyl chloride arereacted. The prodis added. After 5 more minutes of warming, the mixtureuct, 4-pyrroloyl-4'-ureido-diphenyl sulfone is recovered.

1 1 EXAMPLE 29 4-aminomethylcarbonylamino-4'-ureido-diphenyl sulfone Theamide prepared in Example 22, 4chloroacetamido- 4'-ureido-diphenylsulfone, (5 g.) is dissolved in 250 ml. of concentrated ammoniumhydroxide and 250 ml. of ethanol and heated at reflux for 2.5 hours. Theethanol is then removed by evaporation at reduced pressure. The residueis a semi-solid mass which is not filterable. After drying, a solidproduct is obtained which is then washed with water. The final product,4-aminoethylcarbonylamino-4-ureido-diphenyl sulfone, M.P. 240-245 dec.,is analyzed and identified as the hydrate form.

EXAMPLE 30 4-(a-amino-;3-phenylpropionylamino)-4-ureido-diphenyl sulfoneTo 2.91 g. of 4- (sulfanilyl)phenyl urea dissolved in 20 ml. of drypyridine is added with stirring 3.2 g. of phthalyl-L-phenylalanylchloride [J .A.C.S. 74, 38-2 (1952)]. A crystallineproduct begins to form after a few minutes. After a few hours, water isadded to complete crystallization. The crude product is collected on afilter and washed well with water to yield 4.51 g. A portioncrystallized from methanol and has a melting point of 170175 dec. Thisproduct is identified as the intermediate: 4-[4- (phthalyl Lphenylalanylamino)phenylsulfonyl]phenyl urea.

A mixture of 1.14 g. (0.002 mole) of 4[4-(phthalyl-L-phenylalanylamino)phenylsulfonyl]phenyl urea and 0.15 g. (0.003 mole)of hydrazine hydrate in 20 ml. of ethanol is heated at refluxtemperature for 3 hours. The reaction mixture is concentrated underreduced pressure to leave a solid residue. It is then extracted withpotassium hydroxide solution to remove phthalylhydrazide, a by-productof the reaction. The alkali-insoluble material is washed with water andethanol and dried, yield 0.79 g. A 0.26 g. sample is crystallized fromdimethyl sulfoxide and water. There is obtained 0.13 g., M.P. 235-240(dec.), of the product,4-(a-amino-B-phenylpropionylamino)-4-ureido-diphenyl sulfone. Thin-layerchromatography indicates a single component. Analytical data as well asNMR and IR spectra are consistent for the assigned structure.

EXAMPLE 31 4-aspartylamino-4-ureido-diphenyl sulfone A 5.82 gram portionof 4-(sulfanilyl)phenyl urea is dissolved in 50 ml. ofdimethylformamide, the solution is cooled with an ice bath and 4.12grams of dicyclohexylcarbodiimide is added. The mixture is cooled andstirred, and a solution of 6.22 grams of t-butyl-L-aspartic-4- benzylester in 50 ml. of ethylacetate is added in two minutes. After stirringhours under a nitrogen atmosphere at room temperature, the insolubleprecipitate is removed by filtration and the filtrate is concentrated invacuo to -30 ml. volume, which is washed with 100 ml. of ether. Theresidual gum is extracted with 100 ml. of chloroform. Thechloroform-soluble material is chromatographed in 150 grams of silicagel, yielding 1.2 grams of 4[N-(o-benzyl-S-butoxycarbonylamineaspartyl)sulfanilyl]phenyl urea, whichwas pure by TLC but contained residual chloroform, M.P. -95115 C.

A 800 mg. portion of4-[N-(o-benzyl-t-butoxycarbonylamineaspartyl)sulfanilyl]phenyl urea ishydrogenated in 40 ml. of ethanol in the presence of 80 mg. of acatalyst (10% palladium in carbon) at atmospheric pressure. Removal ofthe catalyst by filtration and concentration of the filtrate under astream of nitrogen gives a residue which crystallizes on triturationwith ether to give 4-[N- (t-butyloxycarbonylaspartyl)sulfanilyl] phenylurea, which is pure by TLC and NMR, but contains ether as a solvent,M.P. -150-170 C.

A 420 mg. portion of 4-[N-(t-butyloxycarbon'ylaspartyl)sulfanilyl]phenylurea is dissolved in 5 ml. of dimethoxyethane, and the solution iscooled in an ice bath before being saturated with hydrogen chloride gas.After standing 15 hours at room temperature, the solvent is removed invacuo and triturated with ether to give 0.29 gram of4-aspartylamino-4'-ureido-diphenyl sulfone hydrochloride which is pureby TLC and NMR, but contains solvent, M.P. -75 C.

EXAMPLE 32 4-(B-carboxypropionylamino)-4'-ureido-diphenyl sulfone Amixture of 2.9 grams of 4-(sulfanilyl)phenyl urea, 1.0 gram of succinicanhydride, and 60 ml. of methylethyl ketone is heated at reflux for 17hours. After cooling, the crystalline product is filtered and washedwith methylethyl ketone and with ether. Yield: 2.9 grams of sample,recrystallized from methanol-ether, M.P. C. dec. Analysis shows thematerial to be the hemihydrate of4-(fl-carboxypropionylamino)-4-ureido-diphenyl sulfone. The material ishomogeneous by thin-layer chromatography (TLC) and shows an NMR spectrumconsistent with the above structural formula.

EXAMPLE 33 4-(dimethylaminomethyleneamino)-4'-ureidodiphenyl sulfone To20 ml. of dry dimethylformamide in an ice bath is added 2.56 ml. ofphosphorous oxychloride during five minutes. To the resulting solutionis added 4.0 g. of psulfanilylphenyl urea which dissolves immediately. Aprecipitate subsequently forms and after two hours at room temperature,the solid is removed by filtration and washed with dimethylformamide andwith ether. This solid is taken up in 100 ml. of cold water, thesolution filtered, and the filtrate brought to pH 8 with aqueous sodiumhydroxide. The product is filtered, washed with water, and dried invacuo. Yield of the intermediate N'- dimethylaminomethylene-N -[p(dimethylaminomethylenesulfanilyl)phenyl]urea is 3.85 g., M.P. (frommethanol) ZOO-201 C. Analysis, NMR, and infra-red spectra are consistentwith the assigned structure.

A mixture of 300 mg. of N-dimethylaminomethylene- N [4 (pdimethylaminomethylenea'minophenylsulfanilyl)phenyl]urea and 3.0 ml. of2.5 N hydrochloric acid is heated at about 95 C. (steambath) for 20minutes. The mixture is cooled, filtered, and the crystalline productwashed with cold 2.5 N hydrochloric acid, ethanol, and with ether toyield 250 mg. A sample is recrystallized from methanol for analysis, andindicates that the product is 4-(dimethylaminomethyleneamino)-4-ureido-diphenyl sulfone. The material is homogeneous by TLC and shows anNMR spectrum consistent with the structure.

EXAMPLE 34 4-(fl-carboxy-fl-acetylaminoethylthiomethylamino)-4'-ureido-diphenyl sulfone, sodium salt, dihydrate To 2.91 g. (0.01 mole)of 4-(sulfanilyl)phenyl urea suspended in 33 ml. of ethanol are added1.5 ml. of 36% formaldehyde solution, 1.8 g. (0.011 mole) of N-acetyl-L-cysteine and three drops of concentrated hydrochloric acid. After 2 /2hours, some oily sticky material separates. The reaction mixture isfiltered through sintered glass. To the filtrate is added a solution ofsodium ethoxide in ethanol until precipitation ceases. At this point,the supernatant liquid has a basic pH. The precipitated product iscollected and Washed well with ethanol and ether. After drying in vacuoover potassium hydroxide, the material weighs 2.66 g., M.P. 205210(dec.). Thinlayer chromatography indicates a single component, andanalysis shows a dihydrate. The compound is identified as 4(B-carboxy-fi-acetylaminoethylthiomethylamino)-4'- ureido-diphenylsulfone, sodium salt dihydrate, and NMR and IR Spectra are consistentwith this structure.

13 EXAMPLE 35 4-benzylamino-4-ureido-diphenyl sulfone 6.0 grams ofdibenzylphosphite is added to 50 ml. of benzene and 3.2 grams ofN-bromosuccinamide. After one hour, insoluble material is removed byfiltration, and the filtrate is concentrated in vacuo to an oil which isdissolved in 30 ml. of carbon tetrachloride. This solution is addeddropwise to a stirred mixture of 2.91 grams of 4- (sulfanilyDphenyl ureaand 100 ml. of benzene. After stirring 2 /2 days, a brown gum iscollected and extracted with 70 ml. of 4:1 chloroformzmethanol. Thisextract is chromatographed twice on silica gel using 4:1chloroformzmethanol as an eluant. The front-running fraction yieldsone-half gram, which is recrystallized from methanol to give 0.25 gramof 4-benzylamino-4-ureido-diphenyl sulfone, M.P. 239-240 C.

EXAMPLE 36 4-cinnamylidene- '-ureido-diphenyl sulfone 4.82 grams of4-(sulfani1yl)phenyl urea is dissolved in 200 m1. of hot methanol and4.2 grams of cinnamic aldehyde is added. The mixture is concentrated to50 ml. and, after standing 15 hours, 3.3 g. of material is collected,which is partially recrystallized from 125 ml. of methanol to give 2.6grams of 4-cinnamylidene-4-ureido-diphenyl sulfone, M.P. 200202 C.

This bis-sodium bisulfite adduct of this compound can be prepared bywarming on a steam bath 2.03 g. of 4-cinnamylidene-4-ureido-diphenylsulfone and 1.05 g. of sodium bisulfite in ml. of water. Insolubles areremoved by filtration; the filtrate is dried to a residue andrecrystallized from methanol/ether. The product,4-cinnamylidene-4'-ureido-dipheny1 sulfone, bis bisulfite adduct isidentified, and has an M.P. of 231-234 C.

EXAMPLE 37 4-(Z-nitrophenylsulfenylamino)-4'-ureido-diphenyl sulfone Amixture of 2.0 g. of 4-(N-sulfanilyl)phenyl urea, .71 g. oftriethylamine, 1.3 g. of 2-nitrophenylsulfenyl chloride, and .73 g. oftriethylamine were stirred overnight in 250 ml. of acetone. The mixtureis stirred two more days with the addition of four 1.3 g. portions of2-nit1'ophenylsulfenyl chloride and .71 g. of triethylamine. Insolublematerial is removed by filtration and the acetone is removed in vacuo.The residue is washed with two 200 ml. portions of hot ether and thenextracted with 50 ml. of acetone. The acetone extract is concentrated toa gum which is extracted with 50 ml. of chloroform. The chloroformextract is chromatographed on 100 g. of silica gel using 1% methanol inchloroform. In this manner, 300 mg. of material which is characterizedby its NMR spectrum is obtained, M.P. 90 C., identified as4-(2-nitrophenylsulfenylamino)-4'-ureido-diphenyl sulfone.

1 4 EXAMPLE 38 4- l-methyl-1,2-buteny1-3-one)-amino-4'-ureidodiphenylsulfone A 2 g. portion of 4(sulfanilyl)phenyl urea is stirred for 12hours in 20 ml. of 2,4-pentanedione in the presence of a few mg. of2,4-dinitrobenzene sulfonic acid. The resultant precipitate is collectedon a filter and recrystallized from 35 m1. of 2,4-pentanedione to give1.2 g. of product,4-(1-rnethyl-1,2-butenyl-3-one)-amino-4'-ureidodiphenyl sulfone, M.P.204-207" (1.

What is claimed is:

1. Novel diphenyl sulfones which have the following structure:

wherein R is a phenyl group optionally substituted with chloro, hydroxy,and loweralkoxy, or hydroxy and chloro, or pyrrolyl-, pyridinyl-,furanyl-, pyranyl-, thienyl-, or thiapyranyl-.

2. The compound of claim 1 in which R is a phenyl group optionallysubstituted with chloro, hydroxy and loweralkoxy, or chloro and hydroxysubstituents.

3. The compound of claim 2 in which R is a phenyl group having hydroxyand loweralkoxy substituents.

4. The compound of claim 3 in which R; is 2-hydroxy- 3-methoxyphenyl.

5. The compound of claim 2 in which R is phenyl.

6. The compound of claim 2 in which R is phenyl havingl-hydroxy-S-chloro substituents.

7. The compound of claim 1 in which R is pyridinyl.

8. The compound of claim 1 in which R; is thienyl.

9. The compound of claim 1 in which R is furanyl.

References Cited UNITED STATES PATENTS 2,328,548 9/1943 Dohrn et a1260-3976 2,351,936 6/1944 Dohrn et a1. 260-397.6

FOREIGN PATENTS 491,265 8/1938 England 260*397.6

OTHER REFERENCES Buttle et al., Biochem. 1., vol. 32, pp. 1101 to 1110(1938).

JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R.

